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Published in final edited form as: Alcohol Clin Exp Res (Hoboken). 2024 Jan 23;48(3):507–515. doi: 10.1111/acer.15263

Effects of prazosin treatment on liver enzymes are moderated by alcohol withdrawal symptoms in individuals with alcohol use disorder in a randomized controlled trial

Bradford S Martins a,b, Nia Fogelman a,b, Marshall Tate a,b, Gretchen H Hermes a,b, Rajita Sinha a,b
PMCID: PMC10939766  NIHMSID: NIHMS1957304  PMID: 38258493

Abstract

Background:

Alcohol use disorder (AUD) is associated with significant liver pathology marked by elevated liver enzymes. Prazosin, an alpha1-noradrenergic antagonist significantly improves alcohol drinking outcomes in those with significant alcohol withdrawal symptoms (AW), but effects on liver enzymes are not known. This study assessed the effects of prazosin versus placebo treatment on the liver enzymes alanine transaminase (ALT), aspartate transaminase (AST), and gamma-glutamyltransferase (GGT) in individuals with AW.

Methods:

Participants with AUD were enrolled in a 12-week randomized controlled trial and received either placebo or 16 mg/day of prazosin. Whole blood was drawn to measure liver enzyme levels every 4 weeks, and severity of AW was assessed weekly. Analysis predicting liver function outcomes were tested using linear mixed effects models.

Results:

Controlling for alcohol consumption, a significant AW X treatment effect was seen for ALT (p < 0.05), AST (p < 0.05) and GGT (p < 0.01). Additionally, AST (b = 0.2, p<0.01), ALT (b=0.2, p<0.05), and GGT (b= 0.3, p<0.01) were elevated in those with higher AW in the placebo but not in the prazosin group (AST: p>0.66; ALT: p>0.65). Only in the prazosin group were lower GGT levels associated with higher withdrawal severity (b=−0.16, p<0.05).

Conclusions:

Our findings show a strong interaction effect between alcohol withdrawal symptoms and prazosin treatment on liver function, which were not influenced by week in the trial nor amount of alcohol consumed. Together, these findings suggest that prazosin treatment improves liver enzymes over the course of AUD treatment among individuals with significant AW.

Keywords: Alcohol use disorder, alcohol withdrawal, prazosin, aspartate transaminase (AST), gamma-glutamyltransferase (GGT)

1. INTRODUCTION

Alcohol-related deaths are the third-leading preventable cause of death in the United States with over 140,000 people dying annually (CDC, 2022). In 2010, alcohol use disorder cost the U.S. $249 billion, much of which is due to excess alcohol consumption associated with several chronic medical conditions (CDC, 2022; Sacks et al., 2015). In particular, chronic and heavy alcohol use is associated with significant liver pathology including cirrhosis and alcohol-related liver disease (Conigrave et al., 2003). Incidence of chronic liver disease has significantly increased in the past decade and is now the 5th leading cause of death in adults 45-65 in the United States, with alcoholic liver disease accounting for over half of all liver disease morbidity and mortality (CDC, 2022; Xu et al., 2022).

Despite widespread clinical use, the efficacy of medications used to treat alcohol use disorder (AUD) is limited, with about two thirds of patients experiencing relapse within one year (Hasin et al., 1990). Even without pharmacotherapy, the liver can successfully rejuvenate after mild to moderate alcohol-induced damage if an individual is able to abstain from alcohol; however, approximately half of patients with AUD experience alcohol withdrawal when drinking is reduced or stopped (Goodson et al., 2014). Individuals with severe alcohol withdrawal symptoms (AW) can develop withdrawal-related seizures and delirium, also known as delirium tremens (DT), which can have mortality rates as high as 20% if they do not receive appropriate medical treatment (Turner et al., 1989). Many people continue to drink in order to avoid these symptoms, such that withdrawal negatively reinforces continued alcohol use even in patients who are motivated to stop (Litten et al., 2015; Milivojevic and Sinha, 2018).

Previous research by our group found a significant interaction effect between AW and AUD treatment with prazosin versus placebo indicative of AW moderation of prazosin efficacy (Sinha et al., 2021). Our results showed that prazosin vs placebo treatment only benefited individuals with high alcohol withdrawal symptoms (4 or more alcohol withdrawal symptoms). While previous prazosin randomized clinical trials have shown mixed results, with some studies finding prazosin is associated with decreased number of heavy drinking days and number of drinks consumed in individuals with AUD, and others reporting negative findings, none of these studies assessed the role of AW in alcohol treatment efficacy (Petrakis et al., 2016; Simpson et al., 2018; Wilcox et al., 2018). At the end of our study the AW prazosin group had a 73.5% decrease in drinking days and an 86% decrease in heavy drinking days, while no significant medication effect was observed between the two treatment groups in individuals with low withdrawal symptoms (Sinha et al., 2021).

Prazosin is a non-selective antagonist of alpha-1 adrenergic receptors that are known to be involved in regulation of hepatocyte proliferation and liver regeneration after hepatic injury (Cruise et al., 1987; Michalopoulos and DeFrances, 1997). Interestingly, prazosin has been found to preserve liver function and decrease inflammatory and apoptotic factors in hepatocytes (Khajepour et al., 2023), but studies have also shown that by blocking alpha-1 adrenergic receptors, prazosin decreases DNA synthesis and rejuvenation of damaged liver cells (Cruise et al., 1987; Han et al., 2008). Elevated liver enzymes and inflammatory markers are both released into the bloodstream by alcohol-damaged liver cells (Kerner et al., 2005) and are associated with greater AW and higher risk of developing DT (Borah et al., 2017; Goodson et al., 2014; Vatsalya et al., 2023; Wetterling et al., 1994; Yen et al., 2017). Because AW is associated with inflammation and elevated liver enzymes, prazosin’s anti-inflammatory properties may particularly benefit those with greater AW by improving liver cell function. No previous research has assessed whether prazosin treatment improves liver enzymes in AUD.

If prazosin acts as a protective factor against liver damage in AW, whether it improves liver functioning as measured by liver enzymes, independently or secondarily related to reductions in alcohol consumption remains unclear. The present study reports on secondary analyses from our original study and extends our previous report on prazosin’s effect on drinking outcomes moderated by AW (Sinha et al., 2021) by further assessing prazosin versus placebo effects on the liver enzymes alanine transaminase (ALT), aspartate transaminase (AST), and gamma-glutamyltransferase (GGT). We hypothesized prazosin would decrease liver enzyme levels in participants with AW through anti-inflammatory hepatoprotective effects independent of alcohol consumption.

2. MATERIALS & METHODS

2.1. Participants

Participants consisted of 92 men and women (n=58 men) 18-65 years old (mean=40.56, SD=10.76) who were recruited through referrals from addiction treatment centers in New Haven, Connecticut, and surrounding areas or who responded to ads in newspapers, online, or on social media. Participants had to meet DSM-IV-TR criteria for alcohol dependence as determined by the Structured Clinical Interview for DSM-IV-TR (First et al., 2011), be able to give written informed consent, and be able to read and write in English. Exclusion criteria included meeting DSM-IV-TR criteria for current dependence on any other psychoactive substance aside from nicotine and caffeine; current use of psychoactive medications including antidepressants (except SSRIs), anxiolytics, naltrexone, and disulfiram; any current psychiatric disorder requiring specific medications or hospitalization; significant underlying medical conditions such as cerebral, renal, thyroid, hepatic, or cardiac pathology, pregnancy and hypotension, as indicated by a sitting blood pressure below 90/60 mmHg. All participants signed a written informed consent, and study procedures were approved by the Human Investigation Committee of the Yale University School of Medicine. This study was registered on clinicaltrials.gov (NCT00585780) where the clinical protocol summary can be found.

2.2. Procedures

After being deemed eligible, participants were enrolled in a 12-week randomized controlled trial (RCT) where they received either placebo or 16 mg/day of prazosin (Figure 1). To receive the medication participants had to present with a negative alcohol breathalyzer test at first day of dosing; however, there was no minimum abstinence requirement. The average duration of abstinence at time of first dosing visit was 2.2 days (n=92). Because there was no AW cutoff for study inclusion, participants were given the choice of a fully outpatient treatment or an initial inpatient period followed by a transition to outpatient treatment for the remainder of the study period. Individuals opting (or recommended due to need for treatment of AW) for inpatient stay were admitted to the Clinical Neuroscience Research Unit for 3- to 4-weeks and were initiated on study medication only after completion of medical treatment for alcohol withdrawal. At time of first initial dose and baseline measures, no participant was still receiving medications for AW.

Figure 1.

Figure 1.

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CONSORT diagram

Study medicine assignment was conducted by the Yale Stress Center biostatistician using an urn randomization procedure that balanced groups on gender, age, nicotine smoking status, years of education, and history of anxiety disorders and PTSD. Prazosin dose was titrated over the course of 2 weeks as in previous research (Simpson et al., 2009; Sinha et al., 2021), followed by 9 weeks treatment at the target dose of 16mg/day, with a 5-day titration period in week 12. A Yale Investigational Drug Service pharmacist formulated identical matched tablets of prazosin and placebo and provided dosing for each subject, in weekly blister packs labeled by day and time of dosing, to study staff for dispensing. All patients and study personnel, including investigators, physicians, and study staff, remained blind to medication group. Patients received counseling and support throughout the trial as described in Sinha et al. 2021 (Sinha et al., 2021).

Vital signs, alcohol breath tests, and medication adherence were assessed twice weekly. Liver function was assessed at baseline and approximately every 4 weeks during the trial. During physical exam at baseline and at weeks 4, 8, and 12, 8mL of whole blood was drawn to measure liver enzyme levels. The blood was processed in a room temperature centrifuge and the serum was placed in a separate test tube and sent to Quest Laboratories for assessment of liver enzyme levels using standard medical testing procedures.

2.3. Assessment Measures

The primary outcome measures of alcohol consumption in the original data analysis (Sinha et al., 2021) and further explored in the present study were percent drinking days (DD) and percent heavy drinking days (HDD) as measured by the timeline follow-back assessment (Sobell and Sobell, 1992). Drinking days were defined as any alcohol consumption on a given day and heavy drinking days were defined as 4 and 5 drinks in a given day for women and men, respectively, as per NIH-NIAAA guidelines. Number of alcoholic beverages consumed on each day (AvgD) were additionally included as a secondary outcome. The DD, HDD, and AvgD corresponding to a given timepoint in the data analysis were calculated for the week prior to a blood draw collecting liver enzyme levels.

Participants were assessed by trained research staff on level of alcohol withdrawal symptoms using the Clinical Institute Withdrawal Assessment for Alcohol-Revised (CIWA) (Barbosa et al., 2018). The CIWA is a validated (Sullivan et al., 1989) 13-item assessment that assesses physiological signs (pulse, diastolic and systolic blood pressure) and symptoms (headache, nausea/vomiting, sweating, tremor), psychological symptoms (anxiety, agitation, orientation) and visual, auditory, and tactile sensory disturbances. Items range from 0, no evidence of symptoms, to 4, the highest severity for each symptom. A symptom was considered positive if a participant scored a 1 or more on that item. Individuals with an alcohol withdrawal score > 15 are at increased risk for severe alcohol withdrawal, with increasing scores corresponding to increasing risk of alcohol withdrawal and DT (Young et al., 1987). CIWA was administered at intake and weekly throughout trial duration. There was no CIWA cutoff for participants to be included in the study.

2.4. Data Analysis

Data were cleaned and analyzed in R v.4.2.1 (R Core Team, 2023). Baseline CIWA scores were compared across treatment groups using a two-sample Student’s t-test. To assess the relationship between alcohol consumption (DD, HDD, and AvgD), CIWA scores, and liver enzyme levels at baseline, prior to treatment, linear mixed effects models were generated using baseline variables and controlling for Age and Sex as in the initial report (Sinha et al., 2021). Outcome variables for all models were natural log transformed due to non-normality of model residuals.

Medication (placebo v. prazosin) by Week by CIWA score models predicting liver function outcomes were tested using linear mixed effects models with a random intercept (Kuznetsova et al., 2017). Liver enzymes and alcohol consumption measures during study participation were based on the study week corresponding to the last timepoint at which liver enzymes were drawn (either weeks 4, 8, or 12) to include participants who may have dropped out as well as completers. Liver function data were captured at four timepoints (intake/baseline, Weeks 4, 8, and 12) and each of these timepoints including baseline were included in the LME models to assess medication effect on liver enzymes. Due to variability in participant availability, Week 4 timepoints included a sample in Week 5 (1 participant), Week 8 included 3 participants whose second sample was drawn between Week 5-Week 10, and 8 participants whose Week 12 samples was drawn between Week 10-Week 11. Continuous CIWA withdrawal scores were mean centered to remove non-essential multicollinearity (Iacobucci et al., 2016) and corresponded to timepoints of blood draws. Models controlled for Age and Sex, and Week was assessed as a categorical variable to determine if there were any non-linear effects of time.

Post-hoc analysis was performed in which DD and HDD were also included in the model to control for ongoing alcohol consumption during treatment, as these variables were found to be altered by treatment in our original analysis (Sinha et al., 2021). Individuals who only had baseline enzymes drawn were not included in the analyses as no treatment had been initiated at this timepoint. Outcome variables were natural log transformed. To further describe the specific relationship between alcohol consumption and liver enzymes in each treatment group during study participation, Pearson correlation coefficient was calculated between liver enzymes and DD, HDD, and then average number of drinks consumed separately for placebo and prazosin groups.

3. RESULTS

3.1. Participants

Between November 1, 2012 and May 30, 2017, 92 participants (48 receiving prazosin) who entered the RCT and provided at least one blood sample for liver enzyme levels were included in the analysis. The groups did not significantly differ on sex, race, age, or baseline metrics of alcohol use including liver enzymes (Table 1).

Table 1:

Baseline demographics and clinical characteristics of AUD for study participants

Characteristic Total
(N=92)		 Prazosin
(N=48)		 Placebo (N=44)
N (%)
Male 58 (63.0) 28 (58.3) 30 (68.1)
Race
White 36 (39.1) 21 (43.8) 15 (34.1)
Black 48 (52.2) 23 (47.9) 25 (56.8)
Other 8 (8.7) 4 (8.3) 4 (9.1)
Mean (SD)
Age (years) 40.6 (10.8) 39.6 (11.0) 41.6 (10.6)
Years of Education 13.38 (2.38) 13.5 (2.9) 13.2 (1.7)
Years of Alcohol Use 16.5 (9.7) 15.0 (8.1) 18.1 (11.0)
Past 30-Day Alcohol Use (days) 20.4 (8.5) 20.4 (8.8) 20.6 (8.2)
Average Drinks per Day 8.7 (6.1) 7.8 (4.9) 9.7 (7.4)
CIWA-Ar Score 3.8 (5.0) 3.7 (5.6) 3.8 (4.3)
Liver Function U/L
Alanine transaminase (ALT)a 37.5 (67.9) 43.4 (86.5) 30.9 (37.5)
Aspartate transaminase (AST)a 32.1 (36.2) 34.6 (39.4) 29.3 (32.3)
Gamma-glutamyltransferase (GGT)b 54.5 (69.0) 48.7 (42.9) 61.3 (90.4)
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a

Total N = 85; prazosin N = 45; placebo N = 40

b

Total N = 84; prazosin N = 45; placebo N = 39

3.2. Baseline Withdrawal and Liver Enzymes

There were no significant differences between treatment groups in any baseline enzyme levels (p >0.40). Specific alcohol withdrawal symptoms and CIWA scores at baseline are shown in Table 2. There were no significant differences in CIWA scores between medication groups at baseline (p > 0.92). As reported previously (Sinha et al., 2021), significant associations were found between withdrawal symptoms and alcohol craving (p < 0.0001) and alcohol consumption (p < 0.01) at baseline. Significant positive interactions were observed between baseline alcohol consumption, CIWA scores, and AST (DD: F(1, 1.50) = 5.17, p < 0.05; HDD: F(1, 1.62) = 6.05, p < 0.05), ALT (DD: F(1, 2.09) = 4.06, p < 0.05; HDD: F(1, 2.54) = 5.24, p < 0.05), and GGT (DD: F(1, 3.14) = 6.48, p < 0.05; HDD: F(1, 3.85) = 8.38, p < 0.01) across all participants.

Table 2.

Baseline withdrawal symptom scores as measured by the Clinical Institute Withdrawal

Withdrawal Symptom Number Experiencing (%) Average Symptom Score SD
Tremor 39 (42.4) 1.8 0.8
Anxiety 36 (39.1) 2.4 1.6
Agitation 18 (19.6) 2.8 1.6
Sweating 14 (15.2) 1.5 0.9
Headache 9 (9.8) 3.8 1.9
Nausea/Vomiting 6 (6.5) 2.8 1.6
Tactile Disturbances 5 (5.4) 1.8 0.8
Visual Disturbances 6 (6.5) 1.7 0.8
Auditory Disturbances 5 (5.4) 2 1.2
Orientation 3 (3.3) 1.3 0.6
Systolic BP (mmHg) - 132.2 17.1
Diastolic BP (mmHg) - 77.4 12.0
Heart Rate - 74.6 13.7
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Assessment for Alcohol Scale – Revised (CIWA-Ar). Symptom severity was measured on a scale of 0 to 4 for each symptom with zero representing absence of symptom and 4 being the most severe form of each symptom.

3.3. Prazosin Treatment Effects on Liver Enzymes

Significant Medication by AW interaction effects controlling for DD were seen for each of the liver enzymes: AST (F(1, 0.51) = 6.56, p < 0.05), ALT (F(1, 0.56) = 4.11, p < 0.05), and GGT (F(1, 0.86) = 12.42, p < 0.001). Independent of treatment weeks, liver enzyme levels were significantly lower in the prazosin group compared to the placebo group with increasing levels of AW (Figure 1a-1c). Similar interaction effects for Medication by AW were found controlling for HDD with AST (F(1, 0.39) = 5.03, p < 0.05) and GGT (F(1, 0.71) = 10.56, p < 0.01), however the effect was not significant for ALT (F(1, 0.45) = 3.29, p > 0.07). Over the course of the study and controlling for alcohol consumption (see Supplementary Materials), greater withdrawal in the placebo group was associated with elevated AST (b = 0.2, p < 0.01), ALT (b=0.2, p < 0.05), and GGT (b= 0.3, p < 0.01). Conversely, there were no withdrawal severity-related increases during the study in AST (p > 0.66) or ALT (p > 0.65) levels within the prazosin group. Notably, there was a direct significant effect of Prazosin treatment on GGT such that lower GGT levels were significantly associated with increased withdrawal severity (b=−0.16, p < 0.05). The 3-way interaction of Medication by Week (including baseline, week 4, 8 and 12) by AW, was not significant for any of the three liver markers (p’s > 0.56). However, a significant Week main effect was seen for ALT (p < 0.05) and GGT (p < 0.01) across all participants. This effect was driven by significant reductions in enzyme levels from baseline beginning in the initial Weeks of the study (See Supplementary Table 1). Additionally, there were significant differences in enzyme levels between Sex across all participants (AST: t = 4.40, p < 0.0001; ALT: t = 4.52, p < 0.0001; GGT: t = 2.98, p < 0.01) with men showing higher liver enzymes than women overall.

3.4. Alcohol Consumption and Liver Enzymes

Post-hoc exploratory associations specifically examining the relationship between alcohol intake and liver enzymes during treatment found that only in the placebo group (n=33), but not for the prazosin group (n=41), was higher elevated AST and GGT liver enzymes significantly positively correlated with HDD (AST: r = 0.36, p <0.05; GGT: r = 0.42, p <0.05)) while ALT showed a positive trend without significance (r = 0.30, p > 0.08). None of the liver enzymes were significantly correlated with DD (p > 0.1). To better understand this differential relationship of alcohol consumption and liver enzymes during treatment, we additionally examined the association between liver enzymes and average number of drinks consumed in a week. All liver enzymes were significantly positively correlated with number of drinks consumed in the placebo group only (AST: r = 0.46, p <0.01; ALT: r = 0.35, p <0.05; GGT: r = 0.40, p <0.05). No significant associations were observed between any measure of alcohol intake and liver enzymes in the prazosin-treated individuals (see Supplementary Table 2).

3.5. Safety and Adverse Events

As reported in Sinha et al., 2021, prazosin treatment was found to be generally safe and well-tolerated, and there were no significant differences in frequency of adverse events across medication groups. The most common adverse events were pain, dizzy/lightheadedness, headache, nausea/vomiting, and illness. Less than 5% of participants experienced decreased appetite, forgetfulness, bloody nose, weight gain, swollen ankle, and diarrhea. Two participants experienced adverse events that required overnight hospital admission: a participant in the prazosin group had acute alcohol intoxication and a participant in the placebo group experienced weakness and syncope.

4. DISCUSSION

The current findings show a significant interaction effect between alcohol consumption, withdrawal and liver enzymes at baseline such that prior to treatment, liver enzymes and AW were positively related to the amount of alcohol consumed and remarkably we found that prazosin treatment changed this association. There was a strong interaction effect between prazosin/placebo treatment and AW on liver functioning as measured by the liver enzymes. Predictably, the severity of alcohol withdrawal prior to treatment initiation was positively associated with degree of alcohol use, consistent with previous work (Sinha et al., 2021, 2011; Weiss et al., 2001). Notably, the current treatment efficacy findings further revealed that this relationship persisted only in the placebo and not the prazosin treated group during study participation. In individuals receiving prazosin, liver enzyme levels were not significantly influenced by week in the trial nor alcohol consumption during the 12-week trial, nor were there increases in any of the liver enzymes during the trial in those with higher AW. Instead, prazosin treatment was associated with lower GGT levels while controlling for alcohol intake during the trial.

Correlation analysis within only the placebo group showed that all three liver enzymes continued to be significantly associated with the average number of drinks consumed during the trial. Interestingly, none of the liver enzymes were associated with DD, while GGT and AST were significantly positively correlated with HDD in the placebo group. This finding suggests that during trial participation, individuals who received placebo showed higher liver enzymes associated with binge drinking and not any drinking per se. Conversely, prazosin treatment appeared to have changed this relationship significantly as we found no significant association between any measure of alcohol intake and liver enzymes for the prazosin group.

The lack of significance between alcohol consumption and liver enzymes in individuals receiving prazosin compared to placebo suggests that prazosin plays a role in disrupting this positive relationship. The degree to which this disruption occurs appears to be related to both withdrawal severity and specific liver enzyme. As reported previously, there were no significant differences in CIWA scores between medication groups; however, greater reductions in CIWA scores over study duration were seen in the prazosin group when moderated by AW (Sinha et al., 2021). Controlling for alcohol consumption, all three liver enzyme levels in the placebo group increased with greater AW, while liver enzymes were comparatively significantly reduced in individuals with higher AW in the prazosin group. Elevation of pro-inflammatory markers in AW also occur independent of level of alcohol consumption, and are thought of as allostatic load (Girard et al., 2019). Prazosin was recently found to decrease inflammatory and apoptotic factors in liver tissue injury induced by kidney ischemia-reperfusion (Khajepour et al., 2023). As an alpha1-antagonist, prazosin prevents vasoconstriction and lowers portal vein pressure allowing for better perfusion of the liver (Albillos et al., 1995). Previous research has suggested that the increased vasodilation caused by prazosin prevents accumulation of erythrocytes thereby increasing delivery of oxygen and amino acids as well as decreasing ethanol and its toxic metabolites, allowing for greater hepatocellular repair and regeneration (Randle et al., 2008). Our findings are in line with this proposed mechanism, as fewer toxins, pro-inflammatory markers, and lower oxidative stress in liver cells would decrease cell damage and enzyme activation regardless of alcohol intake.

Furthermore, controlling for alcohol consumption, prazosin reversed the association between GGT and withdrawal severity such that increased withdrawal severity was associated with decreased GGT levels. Baseline GGT levels trended lower in the prazosin group (p > 0.40) compared to the placebo group, however Baseline GGT level in both groups were clinically elevated. Treatment x AW interaction effects from the LMEs models showed that significant persistent reductions in GGT levels occurred only with high AW in the prazosin group, while significant reductions in GGT levels did not occur in either the placebo group nor in individuals with low AW. GGT is a biomarker associated with higher severity of alcohol use (Park et al., 2013; Torkadi et al., 2014; van Beek et al., 2014) and disproportionate elevation of GGT compared to AST and ALT is used clinically as a marker of excessive or harmful alcohol use (Agarwal et al., 2016). The observed increase in GGT associated with alcohol consumption in the placebo group is in line with this work. Previously reported findings from the current sample of prazosin’s efficacy on drinking outcomes found that prazosin was associated with decreased number of drinking days and heavy drinking days overall, and only in those with higher AW (Simpson et al., 2018; Sinha et al., 2021; Wilcox et al., 2018). Repeated alcohol use and cessation leads to increased severity of withdrawal symptoms over time (Malcolm, 2003) which are associated with greater levels of GGT in the blood (Borah et al., 2017). Our findings suggest that the prazosin-disrupted relationship between GGT and alcohol consumption may serve as a protective factor against this ‘kindling’ effect, such that GGT levels decrease with greater AW with prazosin treatment.

There was no significant relationship between AST nor ALT and alcohol consumption or withdrawal in individuals who received prazosin, suggesting that prazosin treatment negates the relationship between alcohol consumption, withdrawal, and liver enzymes observed in the full sample at treatment entry and which continued to be evident during treatment only in the placebo group. Research has shown that AST and ALT are less sensitive markers of excessive alcohol use compared to GGT, and elevated AST:ALT ratio is used clinically as an indicator of alcoholic cirrhosis, rather than alcohol consumption (Gough et al., 2015). Because underlying medical issues, including hepatic illnesses, were exclusionary criteria for the study, none of the study participants had been diagnosed with alcoholic cirrhosis and mean AST and ALT levels were within normal limits at all study timepoints including baseline (S. Figure 1). Additionally, liver function most often returns to baseline after a month of abstaining from alcohol use (Thomes et al., 2021; Yen et al., 2017). It is possible that the lack of a significant reduction in ALT and AST in prazosin treated individuals with alcohol withdrawal symptoms was related to participants liver functioning improving during treatment, and these markers becoming less sensitive to the changes in the pattern of alcohol use. Together, along with prazosin reversing the positive association between GGT and alcohol intake, these findings suggest an effect of prazosin treatment efficacy among those with greater alcohol withdrawal severity at intake for improved liver enzymes over the course of treatment.

There were a few limitations in the present study. Importantly, women made up only one-third of the overall sample. While sex was controlled for in the analyses, there was not adequate power to assess sex as an interaction effect with treatment on enzyme levels. Consistent with previous research (Schneider et al., 2013) there were significant differences in enzyme levels between sexes, with men generally having higher enzyme levels than women. Future studies should investigate whether these sex differences in enzyme levels are associated with withdrawal severity and treatment outcomes. Additionally, more individuals in the prazosin group withdrew from the study due to side effects (N=6) than in the placebo group (N=2) as reported in the Sinha et al. 2021 paper, and while this difference was not statistically significant, future studies will need to more carefully assess prazosin related side effects. Although our results support an anti-inflammatory model of prazosin’s effect on liver enzymes in higher AW, we were unable to fully explore this model as pro-inflammatory markers were not collected. Additionally, because liver enzymes were drawn at only 4 timepoints throughout the course of the study, our analyses were limited in our ability to temporally compare the changes in AW symptoms, which closely follow changes in alcohol consumption, with the changes in liver enzymes, that may only occur over weeks to months. While we do not believe that this limits the clinical significance of our findings, future studies should further investigate the cellular mechanism underlying our results.

5. CONCLUSIONS

Despite these limitations, the present study found strong evidence that prazosin alters the relationship between alcohol consumption, the severity of alcohol withdrawal, and liver enzymes, and improves liver enzyme levels in those with higher AW as compared to placebo. It is unclear the extent to which prazosin’s anti-inflammatory properties directly decrease liver enzymes versus the improved liver enzyme levels being due to prazosin effects on metabolism of alcohol that in turn result in lower liver enzyme levels. Future studies should collect more frequent enzyme and inflammatory marker levels during the up-titration of prazosin to better understand this relationship. Prazosin-associated decreases in liver enzyme levels in individuals with AW may help to improve liver functioning either directly or indirectly via decreases in alcohol use, and our findings offer further evidence of the therapeutic mechanism of action of prazosin in the treatment of AUD for those with alcohol withdrawal symptoms.

Supplementary Material

Supinfo

Figure 2:

Figure 2:

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Log-transformed medication (placebo v. prazosin) by CIWA score models predicting liver function outcomes from across all study timepoints including Baseline. Significant decreases in enzyme level between placebo and prazosin groups were found for A) AST, t = 2.77, B) ALT, t = 2.19, and C) GGT, t = 3.66. *p<0.05; **p<0.01; ***p<0.001

FUNDING SOURCE

This work was funded by the National Institute of Alcohol Abuse and Alcoholism grants R01-AA020504 and R01-AA029113 (RS) and National Institute of Mental Health (NIMH) award R25MH071584-14 supporting clinical neuroscience residency training (BM). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIAAA or NIMH.

Footnotes

DECLARATIONS OF INTEREST

The authors BSM, NF, MT, GH and RS have no conflict of interest or financial disclosures relating to the findings of this paper. Dr. Sinha is on the Scientific Advisory Board of Embera Neurotherapeutics and has received research support from Aelis Farma, CT Pharma and Aptinyx, Inc.

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